HU228788B1 - Anti-infective active substance combinations and the use thereof for the topical treatment of fungus diseases of toe and finger nails - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to a combination of an anti-infective agent and a topical application thereof for the treatment of fungal diseases of the foot and hand.

Fungal diseases of the toenails (Onychomykosen) are widespread worldwide. It is in the highly industrialized areas that these diseases are chronic and resistant to individual treatments. Onychomykosen accounts for 40% of the most common nail diseases. According to the state of the art, the incidence of Onychomykosen's disease is 2.8-8.4%. Nail fungus nowadays has approx. 30% of all dermatomycotic diseases. .The epidemiological studies show that 20 to 30% of patients with Tinea pedis also have Onychomykose.

Many patients, especially if the Onychomykose infection is significantly visible on the nails, feel limited in their social contacts. In addition, the disease may limit the patient's tactility, motility and manual skills. Treatment is also necessary because of the fact that in the case of nail infections, this is the origin of the infections.

974 i 0-9449 OE / Hqj can spread to other parts of the wine. Furthermore, the risk of infection is affecting an increasing population.

Since the beginning of the 1980s, many treatment methods have been developed to treat Onyehornykose. On the one hand, these are novel systemically active antimycotics; for example, judraeonazole (US 4 26-179); (B) -N- (6,6-Dimethyl-2-hepten-4-yn-1-yl) -N-methyl-1,1-naphthalen-methanamine, also designated as Terbinafine, and α- (2) , 4-difluorophenyl) -α- (1 H-1,2,4-triazol-1-ylmethyl) -1H-1,2,4-triazol-1-ethanol known as Fluconazole, but these also include topically applied lacquer coatings which appear to be promising for the treatment of mild to moderate infections.

Experience has shown that systemic treatment procedures produce significant, undesirable, often life-threatening side-effects, as the active substance crosses the site of infection through the bloodstream.

Side effects and interactions with other drugs can be pre-programmed in many older patients with multiple illnesses. In addition, systemic antimycotics have additional unwanted side effects, such as a gap in the spectrum of pathogens to be treated, or partial uncertainty of resorption.

Recently, various attempts have been made to train antimycotics in combination with systemic ItraoonazoL and Terbinafine treatment in patients with Onyehomykose infection. The results showed; that in the case of severe Onyehomykose infections, the combination of topical lacquer coatings and systemic administration of bertraeonazole or Terbinafine significantly outweighed therapy with ItraconazoWal and Terblnafine alone. So far, results suggest that systemic treatment failures can be significantly reduced by using a combination of topically effective antimycotic lacquer coatings and systemic antimycotic agents.

The disadvantage of treating with combinations of fopic and systemic antimycotics is the systemic load with all of the associated negative effects that fall on patients in this treatment strategy. Another major disadvantage is the low amount of systemic antimycotic drug that reaches the foot or toenails. In addition, the use of systemic antimicrobial sV has been very costly and drastic so far.

Itraeonazole is administered topically to the foot or toenails in a therapeutically effective concentration (WO 90/19186).

It is an object of the present invention to provide a composition which does not show the disadvantages of treating Ouyehomykose infections with topical / color combination therapy. In contrast to the prevailing technical prediction that systemic antimycotics, such as itraconazole, are capable of penetrating the nail only by topical application of the keratin sulfuric bridges of the nail and the addition of sufficient amounts of carnary anhydride (WO 9/1918) _and surprisingly one By topically applying a combination of a systemic antimycotic in a lacquer line without the aforementioned measures and additives, it will be possible to introduce a therapeutically effective machine blade into the nail. Furthermore, in patients treated with systemic antimycotics, antimycotics are only detectable in trace amounts in the toenails.

Accordingly, the present invention relates to pharmaceutical compositions comprising a combination of a topical and a systemic antimycotic in a physiologically acceptable lacquer coating.

The present invention preferably relates to a pharmaceutical composition comprising at least one of systemic antimycotic salts of Itraconazole, Terbinafm and Fluconazole and / or Cyclopirox, o- (2,4,4-trimethylpentyl) in a water-insoluble film-forming material. -hydroxy-4-methyl-2 - ((1H) -pyridone, Amorolfine and Butenafine and / or physiologically acceptable salts thereof containing a mixture of at least one or more of the above-mentioned anthnychotics.

Preferred are pharmaceutical formulations which include Cielopirox (also referred to as O-cyclohexyl-1-hydroxy-4-methyl-2- (1H) ~ -pyridone) and Itraconazole or Butenafine hydrochloride and Fluconazole or Ciciopirox-. and Fluconazole or Amorolfine hydrochloride and Terbinafine hydrochloride as antimycotics.

The above topical and systemic antimycotics may be used in their free form or in the form of their physiologically acceptable salts. Particularly suitable salts are those formed with organic bases such as non- or poorly volatile bases such as low molecular weight alkanolamines, such as ethanolamine, * ** ». ♦ * '« * ^ψ

diethanolamine, N-ethyl-ethanolamine, N-methyl-diethanolamine, tri-ethanolamine, dimethyl-lamin-ethanol, 2-amino-2-methyl-n-propanol, dimethylaminopropanol, 2-amino-2-methyl-propanediol, triisopropanolamine. Other poorly volatile bases include ethylenediamine, hexamethylenediamine, morpholine, piperidine, piperazine, cyclohexylamine, tri-butylamine, dodecylamine, Ν, Ν-dimethyldodecylamine, stearylamine, oleylamine, benzylamine, dibenzylthiamine, , N-methylmorpholine, N-methylpiperazine, 4-methylcyclohexylamine, N-hydroxyethylmorpholine. Quaternary aluminum ammonium hydroxide salts may also be used, such as trimethylbenzylammonium hydroxide, tetramethylammonium hydroxide or tetraethylammonium hydroxide, and gnanidine or derivatives thereof, especially alkylated derivatives thereof. It is also possible to use low molecular weight alkylamines, such as methylamine, ethylamine or irethylamine, as salt-forming agents. Salts with inorganic cations may also be used, for example, alkali metal salts, especially sodium, potassium or ammonium salts, particularly preferred are hydrochlorides, alkaline earth metal salts, magnesium and calcium salts, and salts with 2-4 cations, in particular zinc, ahimhuum or zirconium salts,

The invention also relates to the use of a combination of topical and systemic antimycotic in a physiologically acceptable lacquer coating, for the preparation of topical pharmaceutical compositions, for use in the prophylactic and therapeutic treatment of fungal diseases of the foot and tooth.

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The invention further relates to a water-insoluble film-forming agent, at least one systemic antimycotic agent, Itaeonazole, Terbinafine and Flneonazole, and / or physiologically acceptable salts thereof, and at least one topical antimycotic agent, Ciciopyroxy- (2-4,4-trimethylpentyl) -1-hydroxy. Methyl-2 ~ (1 H) ~ -pyridine, Amorolfine and Butenafine and / or a physiologically acceptable salt thereof or a mixture of more than one of these antimycotics or salts thereof for the preparation of topical pharmaceutical compositions suitable for the prophylactic and therapeutic treatment of foot and hand fungal infections.

The amount of topical and systemic active ingredients in the lacquer compositions of the present invention will depend on the structure of the particular active ingredient, "their release from the lacquer film", their ability to penetrate the nail ", and their antifungal properties.

In the pharmaceutical compositions of the present invention for the treatment of Onychomykose infections, which are treated with nail polish! are used and use forms containing the solvent quantity of the active ingredient is generally from 0.25 to 20 topical wt% _being preferred. 2-15% by weight. The amount of systemic agent is generally 0.05 to 10% by weight, preferably 0.1 to 5% by weight,

The nail polish of the present invention is in addition to the active ingredient dissolved in the solvent or solvent mixture. " as an important constituent, it also contains one or more film forming agents which, upon drying, form a water-insoluble film on the nail surface.

Suitable film-forming agents include, for example, cellulose nitrate or physiologically acceptable polymerizate-based materials, which are customary in the cosmetic field, for example, preferably in admixture with cellulose nitrate. Examples are: polyvinyl acetate) or partially saponified poly (vinyl acetate), a mixture of crotonic acid or maleic monoalkyl ester of vinyl acetate on the one hand, and polynerates and other vinylacetates and other a mixture of polymerizates, a mixture of a methyl vinyl ether and a mole, a mixture of a polymer of n-acid monoalkyl ester, in particular a maleobutyl ester, a mixture of a fatty acid vinyl ester and an acrylic acid or methacrylic acid, a polymeric acid, a and a mixture of methacrylic acid or alkyl acrylic acid or alkyl methacrylic acid, polyvinyl acetate and polyvinyl 1-butifates, alkyl-substituted poly-N-vinylpyrrolidone k poiimerizáiurnok, olefins and a mixture makdnsavanhidri.dbő.1 polymers · alkyl esters of acrylic acid and a reaction product of rosin and an alkyl ester thereof. In the esters, the alkyl group is generally short-chained and preferably has no more than 4 carbon atoms.

Preferred compositions are those wherein the water-insoluble film-forming ethyl acrylate methyl methacrylate trimethylammonium ethyl methacrylate chloride copolymer, a mixture of acrylic and methacrylic ester polymers comprising methacrylic acid ester trimethylammonium methacrylate.

** Mixture of methyl vinyl ether and maleobutyl ester of methyl vinyl ether and polyvinyl bntiral and sputum of cellulose nitrate Mari Catalyst or Methacrylic Acid .

Suitable physiologically acceptable solvents include those customary in the field of cosmetics, such as hydrocarbons, halogenated hydrocarbons, alcohols, ethers, ketones and esters, in particular acetic acid esters of monohydric alcohols such as ethyl or butyl acetate, optionally aromatic carbon. and / or alcohols such as ethanol or isopropanol. mixture.

The solvent combination is known to be of decisive importance for drying time, spreadability and other important varnish and lacquer properties. The solvent mixture preferably a mixture of a low forráspontó (bp 1 <XPC is obtained) and a medium forrásponté (the boiling point. 15O ^o C values) optionally a small amount of high forrásponté solvent (boiling 2oo ^Ö € values).,

The nail polishes of the present invention may further contain conventional cosmetic additives such as beverages or camphor-based emollients, pigments for coloring or dyeing, pearlescent materials, antifouling agents, sylphonamide resins, lipids, perfumes, e.g. sunscreen, for example! 2-hydroxy-4-methoxybenzophenone, anti-bacterial agents, and keratoPtic and / or keratoplastic agents such as urea, alkotom, enzymes and salicylic acid,

X

The advantage of colored or pigmented nail polishes, for example, is that the compositions according to the invention can be adapted to the beauty needs of the patient and the nail lesions are not visible to a third party.

The water-insoluble nail polishes of the present invention are prepared by dissolving the physiologically acceptable nail polish in an antimycotic form in soluble form. mix and further process the composition if necessary.

The amount of antimycotics in the compositions of the invention, based on the amount of non-volatile ingredients, i.e., film-forming agents, optionally present pigments, plasticizers and other non-volatile additives, and effective antimycotics used is generally 2 to 80% by weight, preferably 1 to 60% by weight. , especially 2% by weight.

The lacquer coatings of the present invention can effectively cure Onyehomykose infections without drug reactions and systemic side effects. Given the therapeutic experience so far, this is a very important recognition. Another advantage is the substantially short treatment time with the composition of the invention. This is particularly evident from the higher systemic antimycotic concentrations in the nail after topical application.

The pharmaceutical compositions of the present invention are also suitable for pro-lactic use against Onyehomykose infections, whereby an appropriate storage of the active ingredient in the nail can be provided so that fungal nail disease does not occur in the presence of fungal contamination. The pharmaceutical compositions used for prophylactic purposes contain minor amounts of therapeutic antimycotics. It is also advantageous for nail polish boil prophylactically used in Onychomykose fungi, also in solvent-containing embodiments, if the active ingredient is present in an amount of 0.25-4% by weight, preferably 04% by weight. The amount of systemic agent is generally 0.05 to 3% by weight, preferably 0.1 to 1% by weight. Compared to systemic monotherapy, significantly less material is required for proper drug storage.

The invention also encompasses the use of the compositions of the invention for cosmetic purposes.

The invention is further illustrated by the following non-limiting examples. Unless otherwise indicated, the amounts given are by weight.

t. example

Amorolfine hydrochloride 5.0%

Terbinafine hydrochloride 2.5%

Acrylic and methacrylic ester mixture polymers with trimethylammonium methyl methacrylate chloride (e.g. Eudragit RL 100) Isopropyl myristate

Isopropyl alcohol

Β «1 enafi n-h i hydrochloride Flneonazole

Methyl vinyl ether and maleic acid

5.0%

5.0%

- Mixture of 1 ί ~ monobutyl ester polymerizate 2.5.0%

From $ 6% 05.0%

Example 3

Ciclopirox 8.0%

Itraconazole 0.5%

Isoporpil myristate 5.0%

With 1,2-Propylene Gel 4.0%

Mixture of methyl vinyl ether and malobutyl monobutyl ester polymerization 7.5%

Ethyl «• aeta 25.0%

Isepropil alkebel 50.0%

Cioloplrox 7.5%

Fluconazole 5.0%

Mixtures of methylmercury and monobutyl ester of maleic acid polymerized 15.0%

Ethyl acetate 30,054

Ethanol 06% 42.5%

And,

The amount of the active compound combination after application of the composition of the invention to the subject's nails, φφ'φφ φ φφ

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week after twice weekly treatment with Example 3, the following values were obtained:

itraeonazole 800 ug / g nail

Celelopirox .40 gg / g nail

After administration of 100 mg Itraeonazole daily for 3 months, it is known in the art that itraeonazole has a concentration of 100 ng / g in nail plates.

As a result, the composition of the present invention exhibits near eight times the concentration of itraeonazole in the nail over a short period of time, as with systemic treatment.

After 2 weeks of treatment twice a week, the following Example 4 results were obtained:

Claims (9)

Patent Claims A composition comprising a water-soluble film-forming agent and an active compound combination comprising: Itraeonazole, Terblnafine and Fluconazole and / or a physiologically acceptable salt thereof comprising at least one antimycotic agent and Celelopyrox, he (2,4,4-trimethylpentyl) -1. "Hydroxy-4-methyl-2 - ((1 ') - pyridone, Amorpholine and Butenafine and / or a physiologically acceptable salt thereof is disclosed by at least one antimycotic agent or a mixture of more than one of said antimycotics or salts thereof. A composition according to claim L, which comprises, as an antimycotic agent, Ciclopirox and tecraconazole or Butenafln hydrochloride and Flueonazole or Ciclopirox and Flueonazole or Amorelfim hydrochloride and Terbinafine hydrochloride. A composition according to claim L or 2, which is a physiologically acceptable lacquer coating which is selected from the group consisting of cellulose nitrate, poly (vinyl acetate) and partially saponified poly (vinyl). acetate) on the one hand and vinyl acetate on the other hand and acrylic acid. or a mixture of crotonic acid or maleic monoalkyl ester, a polymer consisting of vinyl acetate on the one hand and a mixture of cronic acid and vinineodecanoate or crolone and vinyl propionate on the other, acetic acid, methyl vinyl ether and maleic acid monoalkyl ester, blend polymer of N-vinylpyrrolidone.l, a blend of methacrylic acid and methacrylic acid alkyl ester, of acrylic acid and methacrylic acid or ferric acrylic acid 1Oa · X · a mixture of an ester, a poly (vinyl acetate) and a poly (vinyl hutirate), an alkyl substituted poly-N-vinylpyrrolidone, a polymer consisting of a mixture of olefins and maleic anhydride, and the reaction product of rosin and acrylic acid, the alkyl group of the esters generally contains less than 4 lower carbon atoms. The composition of claim 3, wherein the water-insoluble film-forming material is selected from the group consisting of ethyl acrylate methyl methacrylate trimethylammonioethyl methacrylate chloride copolymer, acrylic and methacrylic acid ester blend polymerizate comprising trimethylammoniumethyl methacrylate and blend polymers, polymers of polyvinyl butyral and cellulose nickel, or copolymers of methacrylic acid and ethyl acrylate, 5. A composition according to any one of claims 1 to 6, wherein the amount of Cyclopirox, ε- (2,4,4-trimethylpentyl) -1-hydroxy-4-methyl-2 '(1H) -pyridone, Amorolfine and Butenafm is 0.25-20% by weight, preferably from 2 to 1.5% by weight and from 0.05 to 10% by weight, preferably from 0.1 to 5% by weight, of the antimycotics of the Tercraconazole, Terhinafine and Flueonazole groups. 6. Procedure 1-5. For the preparation of a pharmaceutical composition according to any one of claims 1 to 6, the physiologically acceptable lacquer coating is mixed in solution with the antimycotics and further processed as necessary. Use of a composition according to any one of claims 1-5 for the manufacture of a therapeutic for the prophylaxis and treatment of fungal diseases of the foot and hand. The at least one water-insoluble film former of Itraconazole, Terbinafil and Flnconazole and / or their physiologically acceptable salts according to any one of claims 1 to 5 and Cyclopirrox, 6- (2,4,4-trimethylpentyl) -1- hydroxy-4-methyl-2- (1H) -pyridone, Amorolfine and Butenafine, and / or a physiologically acceptable salt thereof comprising at least one or a plurality of mixtures of said anthelmintic drugs or salts thereof for the prophylaxis and treatment of fungal diseases of the foot and hand topical pharmaceutical compositions. 9. A composition according to any one of claims 1 to 6 for use in cosmetics.